Annual Meeting Proceedings Part 1 - American Society of Clinical ...

482s Lung Cancer—Non-small Cell Metastatic
7508 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM
Clinical activity of crizotinib in advanced non-small cell lung cancer
(NSCLC) harboring ROS1 gene rearrangement. Presenting Author: Alice
Tsang Shaw, Massachusetts General Hospital Cancer Center, Boston, MA
Background: Chromosomal rearrangements of the ROS1 receptor tyrosine
kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1
rearrangements lead to expression of oncogenic ROS1 fusion kinases and
sensitivity to ROS kinase inhibition. We examined the efficacy and safety of
crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS,
in patients with advanced, ROS1-rearranged NSCLC. Methods: Patients
with advanced NSCLC harboring ROS1 rearrangement, as determined
using a break-apart FISH assay, were recruited into an expansion cohort of
a phase 1 study of crizotinib. Patients were treated with crizotinib at the
standard oral dose of 250 mg BID. The objective response rate (ORR) was
determined based on RECIST 1.0. The disease control rate (DCR; stable
disease [SD] � partial response [PR] � complete response [CR]) was
evaluated at 8 weeks. Results: Thirteen patients within the ROS expansion
cohort received crizotinib and all were evaluable for response. The median
age was 47 yrs (range 31–72), and all but one of the patients were
never-smokers. All patients had adenocarcinoma histology. 12/13 patients
were tested for ALK rearrangement and all were negative. The median
number of prior treatments was 1 (range 0–3). To date, the ORR is 54%
(7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first
restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the
time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration
of treatment was 20 wks (range 4�–59�). All responses are ongoing, and
12 patients continue on study. One patient had disease progression at first
restaging and was discontinued from the study. The pharmacokinetics and
safety profile of crizotinib in this group of patients were similar to that
observed in patients with ALK-positive NSCLC. Conclusions: Crizotinib
demonstrates marked antitumor activity in patients with advanced NSCLC
harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation
of NSCLC patients for whom crizotinib therapy may be highly
effective. This study represents the first clinical validation of ROS as a
therapeutic target in cancer.
7510 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM
Discovery of recurrent KIF5B-RET fusions and other targetable alterations
from clinical NSCLC specimens. Presenting Author: Marzia Capelletti,
Dana-Farber Cancer Institute, Boston, MA
Background: Many NSCLCs have driving oncogenic alterations including in
EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. Clinically effective drugs are
approved for EGFR and ALK and clinical trials are underway for other
genomic targets. Thus having a means of identifying genomic alterations in
routine formalin fixed paraffin embedded (FFPE) clinical specimens is
critical. Methods: We sequenced 24 FFPE NSCLC specimens with a next
generation sequencing (NGS) assay that captures and sequences 2574
coding exons of 145 cancer relevant genes plus 37 introns from 14 genes
often rearranged in cancer. Tumors from 643 additional patients were
genotyped for KIF5B-RET. Results: We identified 50 alterations in 21 genes
with at least one in 83% (20/24) of tumors (range 1-7). In 72% (36/50) of
NSCLCs, at least one alteration was associated with a current clinical
treatment or targeted therapy trial, including mutations in KRAS, BRAF,
EGFR, MDM2, CDKN2A, CCNE1, CDK4, NF1 and PIK3CA. We also found
an 11,294,741 bp pericentric inversion on chromosome 10 generating a
novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET
(K15:R12) in a Caucasian never smoker. This fusion gene contains the
kinesin motor and coiled-coil domains of KIF5B and the entire RET tyrosine
kinase domain. In 643 additional tumors we identified 11 fusion positive
patients who were all wild type for known oncogenes (frequency of 6.3%
(10/159)). Four unique KIF5B-RET variants were found: 8 K15:R12, 3
K16:R12, 1 K22:R12 and 1 K15:R11. We introduced K15:R12 into
Ba/F3 cells and observed IL-3 independent growth consistent with oncogenic
transformation. KIF5B-RET Ba/F3 cells were sensitive to sunitinib,
sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET,
but not gefitinib, an EGFR kinase inhibitor. Sunitinib, but not gefitinib,
inhibited RET phosphorylation in these cells. Conclusions: We identified
both known and novel genomic alterations from NSCLC FFPE specimens
using a single test. Our findings suggest that RET inhibitors should be
tested in prospective clinical trials in NSCLC patients bearing KIF5B-RET
rearrangements and that NGS is a feasible approach to stratifying patients
for treatment based on their genomic profiles.
7509 Clinical Science Symposium, Sat, 8:00 AM-9:30 AM
Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in
patients with advanced non-small-cell lung cancer (NSCLC). Presenting
Author: Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins University, Baltimore, MD
Background: BMS-936558 is a fully human mAb that blocks the programmed
death-1 (PD-1) co-inhibitory receptor expressed by activated T
cells. We report here that BMS-936558 mediates antitumor activity in
heavily pretreated patients (pts) with advanced NSCLC, a tumor historically
not considered to be responsive to immunotherapy. Methods: BMS-936558
was administered IV Q2WK to pts with various solid tumors, including
NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort
expansion. Pts with advanced NSCLC previously treated with at least 1 prior
chemotherapy regimen were eligible. Pts received up to 12 cycles (4
doses/cycle) of treatment or until PD or CR. Clinical activity was assessed
by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 75 NSCLC
pts were treated at 1 (n�17), 3 (n� 19), or 10 mg/kg (n�39). ECOG
performance status was 0/1/2 in 24/49/2 pts. Tumor histology was
squamous (n�17), non-squamous (n�52), or unknown (n�6). The number
of prior therapies was 1 (n�9),2(n�20), �3 (n�45), or unknown
(n�1). Ninety-five percent of pts had received platinum-based chemotherapy
and 40% had a prior tyrosine kinase inhibitor. Sites of metastatic
disease included lymph node (n�50), liver (n�12), lung (n�62), and bone
(n�13). Median duration of therapy was 10 wk (max 100 wk). Common
related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus
(7%), dizziness (7%), and anemia (7%). The incidence of grade 3-4 related
AEs was 8%. There was 1 drug-related death due to pulmonary toxicity.
Clinical activity was observed at all dose levels (Table) and in multiple
histologies. Several pts had prolonged SD. Some had a persistent decrease
in overall tumor burden in the presence of new lesions and were not
categorized as responders. At the time of data lock, of 10 OR pts, 3 had
responses lasting �6 mo and 5 were on study with response duration of
1.8-5.5 mo. Conclusions: BMS-936558 is well tolerated and has encouraging
clinical activity in pts with previously treated advanced NSCLC. Further
development of BMS-936558 in pts with advanced NSCLC is warranted.
Dose (mg/kg) na ORb uPRc RRd (%)
1 18 1 - 6
3 18 3 2 28
10
aResponse evaluable pts.
bCR or PR.
cUnconfirmed PR.
dResponse rate [(OR � uPR) ÷ n].
37 6 1 19
7511 Poster Discussion Session (Board #1), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A randomized double-blind trial of carboplatin plus paclitaxel (CP) with
daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor
receptors, or placebo (PLA) in patients (pts) with previously untreated
advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group
study BR29. Presenting Author: Scott Andrew Laurie, Ottawa Hospital
Cancer Centre, Ottawa, ON, Canada
Background: In NCIC CTG study BR24, CED 30 mg/d � CP increased
objective response rate (RR) and progression-free survival (PFS), but there
were concerns regarding toxicity in some pts. BR29 tested a lower dose of
CED 20 mg/d limiting accrual to pts without significant weight loss/
hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced
incurable NSCLC of any histology were randomized to receive CED 20 mg/d
or PLA with up to 6 cycles of C (AUC � 6) P (200 mg/m2 ); non-progressing
pts continued CED/PLA after CP until progression, unacceptable toxicity or
pt request. The primary endpoint was overall survival (OS). An interim
analysis (IA) for PFS was planned after 170 events in the first 260 pts; the
study would continue if the hazard ratio (HR) for PFS was � 0.7. Accrual
continued until the required number of events was reached then held
pending IA. Results: The trial was halted when the IA (n�260) revealed a
HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306
randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%,
adenocarcinoma 64%, squamous 13%, other histology 23%. RR was
significantly higher with CED (52% vs 34 %, p � 0.001). For CED/PLA,
respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30,
p�0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p�0.5)]. Grade �3
hypertension (15% vs 3%, p�0.0002), anorexia (7% vs 1%, p�0.02) and
diarrhea (16% vs 1%, p�0.0001) were all significantly increased with
CED; there were 2 deaths possibly-related to CED [1 each hemorrhage,
leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of
CED to CP increased RR and toxicity, but not PFS or OS.
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